tbuckley/cabot-search huggingface dataset:
Phase 1 clinical trial results for NG-350A, a novel transgene-armed and tumor-selective vector: Differential effects of intravenous (IV) versus intratumoral (IT) dosing on immune pharmacodynamics (PD).
Authors: Minesh Patel, Chris Cox, David Krige, Lyle Walker, Vladimir Evilevitch, Jo Carter, Matthew Thomas, Samantha Bucktrout, Brian Champion, Thomas Lillie, Lee S. Rosen, Aung Naing
Journal: Journal of Clinical Oncology (2023)

2572 Background: Tumor-selective therapeutic viral vectors are often limited to IT delivery. NG-350A, a blood stable adenoviral vector, selectively replicates in tumors and expresses an agonist anti-CD40 payload. We assessed the impact of IV vs IT delivery during the phase 1 FORTITUDE study (NCT03852511). Methods: NG-350A was dose-escalated in separate IT or IV cohorts of patients (pts) with metastatic/advanced epithelial tumors. Pts received either 1 (Day [D] 1) or 4 IT injections (D1, 8, 15, 22) of up to 1x10 12 viral particles (vp) or 3 IV infusions completed in &lt;9 days (doses of 1x10 11 to 6x10 12 vp). Serum samples were taken immediately after dosing (pharmacokinetics [PK]) and during follow-up (PD). Baseline and on-treatment (D15+) tumor biopsies were taken. Results: In total, 25 pts received NG-350A monotherapy, 9 by IT and 16 by IV dosing. Both IV and IT dosing elicited similar anti-drug (virus) antibody responses and limited viral shedding. Peak vp Cmax was variable with IT dosing but dose-related with IV dosing. Vector DNA was detected by qPCR in tumor biopsies after higher IV dose levels (including up to ~7 weeks post dosing) and IT injection. Dose-dependent, sustained and specific increases in inflammatory cytokines related to the expected effects and timing of the anti-CD40 transgene production (IL-12, IL-17A, IL-2, IFNγ) were detected in serum of pts treated at higher IV doses. By contrast, limited evidence of such PD effects was seen with IT dosing. Transgene was not detectable in core needle biopsies; however, a novel serum biomarker assay detected transgene mRNA at D8 or D15 in five pts who received higher IV dose levels. Importantly, both IV and IT dosed NG–350A was well-tolerated, with no treatment-related SAEs occurring in &gt;1 pt and no DLTs at the highest dose levels tested. No evidence of anti-CD40 transgene-related toxicity was seen with IV or IT dosing, with few hepatic AEs and no Grade ≥3 CRS. Follow-up for imaging was limited; however, stable disease was observed in 3/6 pts at IV Dose Level 3. Conclusions: This analysis provides the first clear evidence that an IV-dosed tumor-selective viral vector can drive expression of immuno-stimulatory payloads with functional PD consequences in advanced cancers. The improved PK and PD profile of IV vs IT dosed NG-350A also highlights the benefits of systemic delivery for such vectors. Dose-escalation of NG-350A + pembrolizumab to identify a dose for efficacy assessments continues in the FORTIFY study (NCT05165433). Clinical trial information: NCT03852511 . [Table: see text]
Importance of clinical decision making in precision oncology: Discordance in recommendation between next generation sequencing test vendor and molecular tumour board in India.
Authors: Bhawna Sirohi, Sissmol Davis, Anu R I, Moushumi Suryavanshi, Shaheenah S. Dawood, Pankaj Kumar Panda, Shona Milon Nag, Arunangshu Das, Nitesh Rohatgi, Sanjay Popat, Riyaz N.H. Shah, Cherian Thampy, Aparna Raj Parikh, Siddhartha Yadav, Prashant Mehta, Randeep Singh, Deborah Mukherji, Ramila Shilpakar, Sujith Kumar Mullapally, Aju Mathew
Journal: Journal of Clinical Oncology (2023)

e15050 Background: Molecular tumour boards (MTB) facilitate discussions among medical professionals, scientists, bioinformaticians and geneticists for clinical application of precision oncology, via interpretation of various genomic sequencing studies, most commonly Next Generation Sequencing (NGS). NGS test vendor recommendation may differ from the MTB recommendations. We aim to study the discordance rate between these recommendations. Methods: MTB discussions between April 1, 2021 and December 31, 2021, were retrospectively evaluated. MTBs which assessed NGS reports with or without significant genetic mutations but with drug recommendations were included. NGS testing was done with multiple vendors. Patients from all over India, Nepal, Bangladesh, Dubai and Abu Dhabi were discussed. We excluded MTBs which assessed NGS data without any drug recommendations. We compared therapeutic recommendations provided in the NGS report with the first-choice recommendation in the MTB discussion. Recommendation discordance was defined as disagreement between the NGS recommendation and the first MTB recommendation that either instructed its implementation either immediately or on disease progression. Results: 70 MTB data was studied. 49 MTBs assessing NGS reports of 49 unique patients (median age 54 years; range, 32-82) were included in the study. 13 patients had lung cancer, 10 colorectal, 6 breast, 7 hepatopancreatobiliary, 4 carcinoma of unknown primary and 9 others. 17 did not provide any treatment recommendations and hence were excluded. 4 were discussions based on NGS reports previously discussed in an MTB that was already included in the study, hence were excluded. Recommendation discordance rate was 49% (24 of 49). Conclusions: To our knowledge, this is the first study that assessed discordance rate in recommendations between NGS report and MTB from a low- and middle-income country setting. Accurate clinical translation of complex genomic data is at the forefront of personalized cancer care.
PD-L1 expression in Chinese patients with solid tumor and its correlation with gene alternations.
Authors: Xin Zhang, Jiayu Liu, Xin Zhao, Li Sun, Chuang Liu, Yaxuan Zhang, Pengyao Du, Fanfan Meng, Ling Li
Journal: Journal of Clinical Oncology (2023)

e14640 Background: Immune checkpoint blockade are recommended in more and more solid tumors for first-line or posterior treatment, and PD-L1 expression is a crucial predictive biomarker for immunotherapy. However, the expression can be influenced by many factors. Methods: A total of 1743 Chinese patients with solid tumor was retrospectively identified. The Dako PD-L1 IHC 22C3 pharmDx assay was used to detect PD-L1 protein expression. And Tumor Proportion Score (TPS) ≥ 1% was defined as positive expression, TPS ≥ 50% was defined as high expression. Genomic profiling was performed on tumor tissue and matched peripheral blood samples. Only the tumor subtypes with sufficient sample size were used for correlation analysis. Results: PD-L1 positive expression occurred in 45.6% patients and high expression occurred in 8.1% patients. The highest expression incidences occurred in cervical cancer as of 78.8%, followed by lung cancer (53.8%), esophageal cancer (53.7%) and gastric cancer (42.7%). The PD-L1 expression assessed by TPS was consistent with that assessed by Combined Positive Score (CPS) in multiple tumors. However, it was significantly different in gastrointestinal tumors, especially in colorectal cancer (TPS&gt;1%: 30.4% vs. CPS&gt;1: 80.6%). In addition, gene alternations including TP53, CDKN2A, LRP1B, KRAS and PIK3CA apparently occurred in patients with high PD-L1 expression. Moreover, high tumor mutation burden (TMB-H) was associated with PD-L1 positive expression in these Chinese patients. Besides, no correlation was found between microsatellite instability (MSI) and PD-L1 expression. Conclusions: Our results illustrated genomic correlates of PD-L1 expression in Chinese solid tumor patients. These findings may broaden the application of immune checkpoint blockade to patients harboring specific molecular characteristics.
Urine DNA model to predict response to neoadjuvant immune checkpoint inhibitors combined with chemotherapy in muscle-invasive bladder cancer.
Authors: Hailong Hu, Huanhuan Liu, Gangjian Zhao, Zhe Zhang, Chong Shen, Jiayue Qin, Shanbo Cao
Journal: Journal of Clinical Oncology (2023)

e16594 Background: Neoadjuvant immune checkpoint inhibitors (ICIs) combined with chemotherapy show promise in the treatment of muscle-invasive bladder cancer (MIBC). However, not all patients benefit from the treatment. Urine can overcome shortcomings of tissue-based biomarkers to guide treatment decisions. Methods: Thirty-Three patients were recruited in this study and they received three cycles of tislelizumab 200 mg intravenously on day 1 plus nab-paclitaxel 200 mg intravenously on day 2 every three weeks, followed by surgical treatment. Acornmed 808 panel and shallow whole-genome sequencing were performed to predict the efficacy based on the urine DNA. Results: The urine ctDNA levels (highest variant allele fraction) were significantly lower in responder (CR and PR ) patients than this in non-responder (SD and PD) patients (p &lt; 0.001). In addition, a decrease in chromosomal instability number (CIN) occurred in responding tumors (p = 0.028). Furthermore, ROC curves were used to compare the sensitivity and specificity of efficacy prediction, including the urine ctDNA level and CIN. In the ROC analysis, urine ctDNA level setting with an area under the ROC curve (AUROC) of 0.781 (95% CI 0.603 - 0.905, p = 0.005), achieving 100% sensitivity and 54.6% specificity in efficacy prediction. The ROC curve for CIN achieved a sensitivity of 68.2% and specificity of 72.7% (AUC = 0.731; 95% CI: 0.549-0.870, p = 0.013). Combination urine ctDNA level and CIN achieved a sensitivity of 100%, specificity of 63.6% (AUC = 0.806; 95% CI: 0.631-0.922, p = 0.002), positive predictive value (PPV) of 0.846, and negative predictive value (NPV) of 1.000. Conclusions: The classifier provides a framework for novel biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
Updated safety and efficacy results from the phase I study of either LBL-007 (an anti-LAG-3 antibody) in combination with toripalimab (an anti-PD-1 antibody) or LBL-007 in combination with toripalimab and axitinib in patients with advanced melanoma.
Authors: Xue Bai, Mei Li, Yu Chen, Lu Si, Jing Chen, Xingxiang Pu, Ying Cheng, Zhengyun Zou, Shiwei Zhao, Tao Li, Shengli Cai, Jun Guo
Journal: Journal of Clinical Oncology (2023)

9541 Background: Initial safety and efficacy data of LBL-007 plus toripalimab in patients with advanced melanoma (Part A) have been reported in 2022 ASCO (Abstract 9538). Here we present the updated results of part A and the preliminary results of part B (LBL-007 plus toripalimab with axitinib). Median follow-up was 9.7 months at cut-off data (January 11, 2023). Methods: Patients with advanced melanoma with or without prior therapy were enrolled during Jan 2021 - Aug 2022. This trial comprised 2 parts: Part A, patients received LBL-007 (0.25 - 10 mg/kg for dose escalation; 3 or 6 mg/kg for dose expansion) plus toripalimab at 3 mg/kg (both i.v. Q2W); and Part B, patients received LBL-007 at 3 or 6 mg/kg plus toripalimab at 3 mg/kg (both i.v. Q2W) and axitinib at 5 mg BID. The primary objective was safety, the second objectives were pharmacokinetics, pharmacodynamics and efficacy (per RECIST v.1.1). Results: In part A, 68 patients in total (57 treatment-naïve) were enrolled including 20 patients in dose escalation and 48 patients in dose expansion, and among which, 31 additional patients have been enrolled since 2022 ASCO report. Nineteen (27.9%) patients occurred grade ≥3 TEAEs, the common grade ≥3 TEAEs was anaemia (11.8%). No new safety signals were detected. Among 55 efficacy evaluable treatment-naïve patients (41 with acral, 7 mucosal, 7 others), ORR was 23.6%, DCR was 58.2%, and mPFS was 5.7 months (95% CI: 3.7, 9.5). In part B, 11 patients (10 mucosal, 1 acral) were enrolled. No DLT was observed. Five patients (45.5%) occurred grade ≥3 TEAEs, the common grade ≥3 TEAEs included blood pressure increased (18.2%) and transaminases increased (18.2%). One (9.1%) patient discontinued treatment due to TEAEs. ORR was 45.4% (including 4 mucosal and 1 acral), DCR was 72.7%, and mPFS was 5.5 months (95% CI: 1.8, 9.1). Conclusions: LBL-007 plus toripalimab continued to show promising antitumor activity and manageable safety profile in patients with treatment-naïve melanoma, which support further development in this indication. LBL-007/toripalimab/axitinib combination demonstrated acceptable safety profile and encouraging antitumor activity in patients with mucosal melanoma. Acknowledgements: Junshi Biosciences. Clinical trial information: NCT04640545 .
A phase III, double-blind, non-inferiority, randomized controlled trial of antiemetic prophylaxis for highly emetogenic chemotherapy without dexamethasone: CINV POD study.
Authors: Venkatraman Radhakrishnan, Kritthivasan Venkatakrishnan, Jayachandran Perumal Kalaiyarasi, Gangothri Selvarajan, Nizamudin Mahaboobasha, Paulson Vijaykumar Victor, Malarvizhi Anbazhagan, Deyva Manohari Sivanandam, Swaminathan Rajaraman
Journal: Journal of Clinical Oncology (2023)

12127 Background: Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of highly emetogenic chemotherapy (HEC). Current guidelines recommend the use of dexamethasone (DEX) for prophylaxis, but the effectiveness and safety of a DEX-free regimen for CINV prophylaxis in HEC is not known. Methods: This was an investigator-initiated, double-blind, phase 3 RCT designed to show the non-inferiority of a DEX-free regimen (olanzapine, palonosetron, and fosaprepitant; OPF) compared to the NCCN recommended DEX-containing regimen (olanzapine, palonosetron, and dexamethasone; OPD). Chemotherapy-naive patients aged 18-80 years receiving single-day HEC were randomized 1:1 to receive either the OPD regimen (olanzapine 5 mg once a day on days 1-4, palonosetron 0.25 mg on day 1, and DEX 12 mg on day 1) or the OPF regimen (olanzapine and palonosetron as above, and fosaprepitant 150 mg on day 1). The primary endpoint was to compare complete response (CR) rates for vomiting (no vomiting and no rescue medication) during the overall phase (start of chemotherapy to 120 h). The secondary endpoints were CR for nausea (ESAS), toxicities (CTCAE), and patient reported outcome measures (PROM) using MDASI. Assuming CR for vomiting for the overall phase of 77% (power = 90%, 2-sided alpha = 5%, and non-inferiority margin [NI] = 15%), 175 patients in each arm were required (including 5% dropout). Results: Between May 2022-Dec 2022, 350 patients were randomized and 346 received the study interventions (OPD arm n = 174 and OPF arm n = 172). The most common chemotherapy used was adriamycin/cyclophosphamide (66%) followed by cisplatin (27%). CR rates for vomiting for the overall phase were 48.8% in the OPD arm and 79.6% in the OPF arm (P &lt; 0.001), with an absolute difference of -30.8% and 2-sided 95% CI = (-40.31, -21.24) which was within the pre-defined NI margin of 15% and also showed superiority. The DEX-free arm also had significantly higher CR rates for nausea and total control (vomiting and nausea combined) (Table). There were no significant differences in any grade CTCAE toxicities. PROM for fatigue (P = 0.009) and drowsiness (P = 0.002) were more in the OPF arm in the acute phase, and insomnia (P &lt; 0.001) in the OPD arm in the delayed phase. Conclusions: This study shows that a DEX-free OPF regimen is superior to the DEX-based OPD regimen and should be considered a standard option for CINV prophylaxis for HEC. Clinical trial information: CTRI/2022/03/040906 . [Table: see text]
Rural communities and health professional shortage areas (HPSA) and access to immune effector cellular therapy and lymphoma/myeloma clinical trials.
Authors: Nausheen Ahmed, William Wesson, Dinesh Pal Mudaranthakam, Muhammad Umair Mushtaq, Al-Ola A. Abdallah, Forat Umair Lutfi, Joaquina Celebre Baranda, Sunil H. Abhyankar, Joseph McGuirk, Marc Hoffmann
Journal: Journal of Clinical Oncology (2023)

e18633 Background: The National Health Service Corps (NHSC) has created a shortage designation to identify medically underserved communities. HPSA (Health Professional Shortage Areas) designation identifies an area, population, or facility with inadequate access to healthcare resources such as primary care. Rural-urban continuum codes (RUCC) classify U.S. census tracts using urbanization, population density, and daily commuting. Additionally, there are racial, ethnic, and geographic disparities in enrollment on therapeutic cancer clinical trials. Chimeric antigen receptor T cell (CAR T) therapy has been at the forefront of immune effector cell therapy (IEC) for lymphoma and myeloma. However, it is delivered at specialized centers, and access to specialty centers is known to be a challenge due to financial and geographic barriers. At our institution, trials for CAR-T cell therapy in lymphoma and myeloma are conducted by the IEC disease working group (DWG), while non-IEC trials are conducted by the lymphoma/myeloma DWG. We hypothesized that patients from HPSA and rural communities and HPSA had lower access to IEC and non-IEC trials for lymphoma and myeloma . Methods: Patients enrolled between 1/1/2015 – 2/6/2023 on IEC and non-IEC interventional trials with treatment were included. Disease types included lymphoma (Follicular lymphoma, high-grade B cell lymphoma, diffuse large B cell lymphoma) and myeloma were included. The hypothesis was tested through a t-test. Results: There were 667 total subjects. 503 (75.4%) were non-IEC and 96 (14.3%) were IEC clinical trial participants. The majority in both groups were male (52.7%), White (74.8%), non-Hispanic (86%) .Only 69 (10.3%) pts were from rural areas and 223 (38.9%) were from HPSA communities When stratifying based on RUCC (Table), there is significantly higher rural accrual for IEC trials compared to non-IEC trials. Hispanics from rural areas were lower. There were no African Americans (AA) from rural areas. Conclusions: There is low representation of patients from HPSA and rural communities for IEC and non-IEC lymphoma and myeloma clinical trials. The ethnic and racial inequity in access and enrollment to lymphoma/myeloma trials are pronounced in rural and HPSA communities. Strategies to improve clinical trial enrollment of the underserved rural and HPSA populations is an area of unmet need and will benefit minorities and patients from lower socioeconomic status. [Table: see text]
Enhancing STING activation by cyclic dinucleotide-manganese particles for systemic cancer immunotherapy.
Authors: Xingwu Zhou, Xiaoqi Sun, Wang Gong, Yu Leo Lei, James Moon
Journal: Journal of Clinical Oncology (2023)

2571 Background: Activating the innate immune pathway of stimulator of interferon genes (STING) can elicit potent anti-tumor immunity via the production of type-I interferons (IFN-I). However, cyclic-dinucleotide (CDN) STING agonists have undesirable pharmacological properties. Most CDNs in clinical development are administered intratumorally, thus precluding their applications in treating metastasis, hematologic malignancies, and hard-to-reach solid tumors. Here, we report the development of a new nanoparticle system for the systemic delivery of CDN STING agonists with potent efficacy, favorable pharmaceutical properties, and acceptable safety profiles. Methods: Nutritional metal ions play crucial roles in modulating immune pathways, which could potentially be used for enhancing STING activation. We screened different metal ions and found that manganese ion (Mn 2+ ) achieved strong synergy with CDN STING agonists for inducing IFN-I production. We further developed a new nanoparticle system for co-delivery of Mn 2+ and CDN for systemic cancer immunotherapy. Results: Mn 2+ induced up to 77-fold enhancement in CDN-mediated STING activation. Mixing CDNs with Mn 2+ resulted in the self-assembly of nanocrystals, and the lipid layer coating led to uniform nanoparticles. The resulting STING-activating CDN-Mn nanoparticle (SNP) given intravenously elicited IFN-I responses, attenuated the suppressive functions of myeloid cells, remodeled the immunosuppressive tumor microenvironment, and expanded CD8 + T cells for sustained tumor control. Intravenous SNP therapy resulted in robust anti-tumor efficacy in multiple murine tumor models, including a genetically engineered mouse model of MMTV-PyMT triple-negative breast cancer. We have also demonstrated the robust anti-tumor efficacy of SNP against VX2 head and neck squamous cell carcinomas (HNSCC) in New Zealand white rabbits. Mechanistically, the efficacy of intravenous SNP therapy was dependent on the host STING expression but independent of the tumor STING expression. In addition, the anti-tumor efficacy of SNP was decreased in mice lacking Ifnar1 or Ifngr1 expression in the B16F10 melanoma model, showing the crucial effects of IFN-I and IFN-II responses. Lastly, SNP was effectively uptaken by human PBMCs and elicited IFN-I responses when injected into fresh human tumor biopsies derived from HNSCC patients. Conclusions: SNP empowers highly effective systemic cancer immunotherapy via nanotechnology. It also underscores the potential of utilizing metal ions for immune-mediated disease treatment.
A risk prediction model for cisplatin-induced acute kidney injury in patients with head and neck cancer who receive chemoradiotherapy: A supplement analysis of a phase II/III trial of JCOG1008.
Authors: Yoshinori Imamura, Naomi Kiyota, Makoto Tahara, Takeshi Kodaira, Ryuichi Hayashi, Hiroshi Nishino, Yukinori Asada, Hiroki Mitani, Shigemichi Iwae, Naoki Nishio, Yusuke Onozawa, Nobuhiro Hanai, Akira Ohkoshi, Hiroki Hara, Nobuya Monden, Masato Nagaoka, Shujiro Minami, Ryo Kitabayashi, Keita Sasaki, Akihiro Homma
Journal: Journal of Clinical Oncology (2023)

12104 Background: Cisplatin-induced acute kidney injury (C-AKI) is a common reason for treatment interruption in head and neck cancer patients who receive chemoradiotherapy (CRT). We developed a risk prediction model for C-AKI in patients from a randomized phase II/III trial of JCOG1008, which demonstrated that CRT with weekly cisplatin at 40 mg/m 2 (weekly arm) was noninferior to 3-weekly cisplatin at 100 mg/m 2 (3-weekly arm) in terms of overall survival for postoperative high-risk head and neck cancer ( J Clin Oncol 2022; 40: 1980-90). Methods: Two hundred fifty-one patients received RT with a total of 66 Gy/33 fr concurrently with 3-weekly or weekly cisplatin. AKI was defined using the AKI Network classification/staging system as an increase in serum creatinine of ≥0.3 mg/dL or a 1.5-fold or greater increase from baseline (≥ stage I) by 30 days after the completion of CRT. AKI risk prediction models were developed by combining explanatory variables which were expected to contribute, including age, sex, ECOG performance status, primary site, pathological stage, diabetes mellites, hypertension, main nutritional method, treatment arm, serum albumin, serum magnesium, and creatinine clearance (CCr) at registration. A logistic regression model with the Akaike information criterion was used to explore the optimal model. Results: Ninety-four of 251 (37.5%) patients developed C-AKI in this study. The optimal C-AKI risk prediction model was composed of four factors, including a primary site (hypopharynx/larynx or oral cavity/oropharynx, odds ratio [OR] 1.92 [95% CI, 1.10 to 3.30]), treatment arm (3-weekly arm or weekly arm, OR 1.75 [95% CI, 1.02 to 3.00]), serum albumin (≤ 3.5 g/dL or &gt; 3.5 g/dL, OR 2.06 [95% CI, 1.11 to 3.87]) and CCr ( &lt; 90 mL/min or ≥ 90 mL/min, OR 1.85 [95% CI, 1.05 to 3.26]). The incidence of C-AKI increased in accordance with a total count of the four factors (Table): with a total count of 0-1, 2 and 3-4, the incidence of clinically relevant stage II/III C-AKI was 2.9%, 11.5%, and 22.6%, respectively. When total count was ≤1, the positive and negative predictive values for stage II/III C-AKI development were 16.1% and 97.0%, respectively. Conclusions: We developed a risk prediction model for C-AKI in head and neck cancer patients who receive CRT using primary site, cisplatin administration method, serum albumin, and CCr. The high negative predictive value of this prediction model may help rule out the development of moderate to severe C-AKI. Clinical trial information: jRCTs031180135 . [Table: see text]